One of the largest families of receptors in the human genome is that of the 7 transmembrane receptor (7-TMR) superfamily, also known as G-protein coupled receptors (GPCRs), numbering approximately 2000. G-protein coupled receptors regulate a large number of important physiological processes. At least 40% of the prescription drugs that have been developed have actions related to these receptors. Most of these drugs work by interfering with the ligand binding to the receptor that occurs outside of cells. G-proteins are important effectors of cell activation.
There is now an effort in the scientific community to define compounds that block the intracellular interaction between the receptor and its signal transducing partner, the G-protein.
The second intracellular loop of the 7TMR receptors are known to play an important role in the signal transduction as mutations in this region cause a disturbance in the 7TMR-associated signal transduction.
There has been an attempt (Benovic et al., Br. J. Clin. Pharmac., 30:3s-12s (1990) to interfere with the β2-adrenoreceptor signal transduction by administration of peptides corresponding to the full second loop of this receptor. However, these results were extremely unsatisfactory as the sequence corresponding to the long 2nd loop was virtually inactive in modulating signal transduction with an IC50 of about 240 μm.
Sphingosine 1-phosphate is formed in cells in response to diverse stimuli, including growth factors, cytokines, G-protein-coupled receptor agonists, antigen, etc. Its production is catalyzed by sphingosine kinase, while degradation is either via cleavage to produce palmitaldehyde and phosphoethanolamine or by dephosphorylation. Sphingosine 1-phosphate can also bind to members of the endothelial differentiation gene (EDG) G-protein-coupled receptor family [namely EDG1, EDG3, EDG5 (also known as H218 or AGR16), EDG6 and EDG8] to elicit biological responses. These receptors are coupled differentially via G(i), G(q), G(12/13) and Rho to multiple effector systems, including adenylate cyclase, phospholipases C and D, extracellular-signal-regulated kinase, c-Jun N-terminal kinase, p38 mitogen-activated protein kinase and non-receptor tyrosine kinases. These signaling pathways are linked to transcription factor activation, cytoskeletal proteins, adhesion molecule expression, caspase activities, etc. Therefore sphingosine 1-phosphate can affect diverse biological responses, including mitogenesis, differentiation, migration and apoptosis, via receptor-dependent mechanisms. Additionally, sphingosine 1-phosphate has been proposed to play an intracellular role, for example in Ca(2+) mobilization.
The term “angiogenesis” (also referred to at times as “neovascularization”) is a general term used to denote the growth of new blood vessels both in normal and pathological conditions.
Angiogenesis is an important natural process that occurs during embryogenesis, and in the adult healthy body in the process of wound healing, and in restoration of blood flow back into injured tissues. In females, angiogenesis also occurs during the monthly reproductive cycle to build up the uterus lining and to support maturation of oocytes during ovulation, and in pregnancy when the placenta is formed, in the process of the establishment of circulation between the mother and the fetus. The healthy body controls angiogenesis through the interactions of angiogenesis-stimulating growth factors, and angiogenesis inhibitors, and the balance between the two determines whether angiogenesis is turned “on” or “off”.
In the therapeutic field, there has been in recent years a growing interest in the control of angiogenesis. By one aspect, the aim was to control or diminish excessive and pathological angiogenesis that occurs in diseases such as cancer, diabetic blindness, age related macular degeneration, rheumatoid arthritis, psoriasis, and some additional 70 conditions. In these pathological conditions the new blood vessels feed the diseased tissue, for example the tumor tissue, providing it with essential oxygen and nutrients thus enabling its pathological growth. In addition the pathological angiogenesis many times destroys the normal tissue. Furthermore, the new blood vessels, formed for example in the tumor tissue, enable the tumor cells to escape into the circulation and metastasize in other organs. Typically, excessive angiogenesis occurs when diseased cells produce abnormal amounts of angiogenetic growth factors, overwhelming the effect of the natural angiogenesis inhibitors present in the body.
Anti-angiogenetic therapies developed today, are aimed at preventing new blood vessel growth through the targeting and neutralization of any of the stimulators that encourage the formation of new blood vessels.
A contrasting indication of regulating angiogenesis is the stimulation of production of neovascularization in conditions where insufficient angiogenesis occurs. Typically, these conditions are diseases such as coronary artery diseases, stroke, and delayed wound healing (for example in ulcer lesions). In these conditions, when adequate blood vessels growth and circulation is not properly restored, there is a risk for tissue death due to insufficient blood flow. Typically, insufficient angiogenesis occurs when the tissues do not produce adequate amounts of angiogenetic growth-factors, and therapeutic angiogenesis is aimed at stimulating new blood vessels' growth by the use of growth factors or their mimics.
The main goal of the angiogenesis therapy is to produce a biobypass—i.e. to physically bypass diseased or blocked arteries, by tricking the body into building new blood vessels.